1. Field of the Invention
This invention relates to methods and compositions useful in the treatment of patients suffering from Hodgkin's disease and other conditions such as large cell anaplastic lymphoma and graft-versus-host disease. In particular, this invention relates to antibody-toxin conjugates (immunotoxins) capable of selectively killing Hodgkin's and Reed-Sternberg cells and other cells such as activated lymphoid cells and monocytoid cells, and, in further embodiments, to hybridomas and antibodies useful in the preparation of such immunotoxins.
2. Description of the Related Art
Chemotherapy of Hodgkin's disease is undoubte of the major breakthroughs in clinical oncology over the last 25 years. The introduction of the multi-agent chemotherapy regimens such as MOPP (1) and ABVD (2) and the optimized use of radiation in early stages of the disease has improved the probability of curing these patients from less than 5% in 1963 to about 70% at the present time (3-5).
Despite the high proportion of cures in patients with Hodgkin's disease who respond to first line treatment, the outlook for those who relapse or fail to achieve complete remission is bleak. Second line combination chemotherapy can produce good remission rates although cures are uncommon (6-8). High dose chemotherapy with autologous bone marrow transplantation has been reported to be effective in relapsed or resistant cases of Hodgkin's disease (HD) but is associated with major toxicity, resulting in up to 26% treatment-related deaths (9,10). Of those patients achieving complete remission, 15-20% will develop a second malignancy as a chemotherapy-related side effect (11). There is therefore a need for new modes of treatment for this disease. In particular, there is a need for new agents for the management of or treatment of Hodgkin's disease that are free from mutagenic side effects.
An approach proposed by the present invention to preparing new, non-mutagenic reagents for the therapy of Hodgkin's disease would be to couple the ribosome-damaging A-chain of ricin or other toxins to antibodies directed against Hodgkin cell-associated antigens. In several laboratories, ricin A-chain has been linked to antibodies against tumour-associated antigens to form immunotoxin reagents that are selectively toxic to malignant cells in vitro (reviewed in 12,13). However, in vivo studies in rodents, and more recently, in man have given variable results. In rodents, good antitumor effects have generally been observed in leukemia and lymphoma models, whereas solid tumors appear to be less responsive (12,13). In humans, the antitumor effects obtained in melanoma (14) and leukemia (15) patients have so far been disappointing, whereas in patients with steroid-resistant graft-versus-host disease, remarkable benefit has been obtained (16).
Thus, although there have been many reports of the high cytotoxic potency and specificity of immunotoxins in vitro, relatively few workers have reported good antitumor effects of immunotoxins on solid tumors in vivo: Bernhard et al. (17) and Hwang et al. (18) reported that a single i.v. or s.c. injection of an abrin A-chain immuno-toxin reduced or completely abolished the growth of solid L10 hepatocarcinoma cell line tumors in guinea pigs. Leonhard et al. (19) described 11/46 complete remissions of solid human T cell line tumors in mice intravenously treated with CD5 ricin A-chain immunotoxins. Roth et al. (20) demonstrated a reduction in the number of pulmonary metastases after systemic administration of ricin A-chain immunotoxins to mice bearing TRF (transformed rat fibro-blasts) tumors. Others have needed to give multiple injections with dosages up to 125% of the LD.sub.50 (21) or intratumoral injections to show antitumor effects of their immunotoxins (22). Accordingly, the use of immunotoxin in the treatment of tumour, particularly solid tumors, has heretofore been unpredictable at best.
For the foregoing and other reasons, it can be appreciated that there is currently a need for novel approaches to the treatment and control of patients suffering from Hodgkin's disease. In particular, there is a need for improved treatment modalities which exhibit one or more advantages over existing approaches to treatment. Furthermore, there is a need for treatments which may be employed in those cases where more traditional approaches have not proven effective. The present invention addresses one or more shortcomings in the art through application of immunotoxin technology.